Gastric adenocarcinoma (GC) remains one of the most common forms of cancer and one of the leading causes of cancer-related death worldwide. Approximately six hundred thousand new cases of gastric cancer/year are attributable to Helicobacter pylori infection worldwide, making this bacterial pathogen the strongest known risk factor for gastric malignancy. However, only a percentage of infected individuals develop neoplasia, underscoring the importance of defining mechanisms that regulate tumorigenic interactions between bacteria and infected people. We have developed an innovative hypothesis that establishes a molecular link between the tumorigenic potential of H. pylori and inactivation of the Oncogenic Stress Response pathway (OSR), a major tumor suppressor mechanism that prevents tumorigenic transformation of gastric cells. This hypothesis is supported by strong preliminary data generated by studies of human individuals and animals infected with H. pylori. Our research revealed that suppression of the OSR by H. pylori is strongly linked to gastric carcinogenesis and that tumorigenic H. pylori strains are able to inhibit surveillance by the OSR. We will build on these findings to further investigate the OSR inhibition by H. pylori as a critical factor contributing to development of gastric adenocarcinoma. In aim 1, we will define the molecular underpinning of H. pylori signaling toward inhibition of the OSR. In aim 2, using the animal models and gastric organoids, we will investigate regulation of the OSR in the gastric niche in vivo. In aim 3, we will characterize how natural variability of bacterial virulence factors affects the OSR. We will also test human clinical specimens and H. pylori clinical isolates collected in geographical areas with high and low gastric cancer risk. Taken together, the proposed studies will provide novel insights into tumorigenesis associated with H. pylori infection, investigating the OSR regulation in condition of H. pylori infection. Thi will help to reveal the potential risk factors for gastric tumor development and lay the groundwork for translation of these clinically relevant data into novel therapeutic applications in H. pylori - infected patients.